CNS disorders comprise several major categories as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TM) [3]. Psychotic disorders include schizophrenia, paranoia, and manic-depressive illness. Motor disorders include Parkinson's disease, epilepsy, and Tourette's syndrome. Mood disorders include depression, mania, and bipolar disorder. Anxiety disorders include generalized anxiety, phobias, panic attacks, and obsessive compulsive disorders. Cognitive disorders include autism, mild cognitive impairment (MCI), Attention Deficit Hyperactivity Disorder (ADHD), and dementia. Substance-related disorders include narcotic addiction and withdrawal; and eating disorders such as Anorexia Nervosa, bulimia, and obesity. Other disorders involving CNS include sleep disorders, endocrine disorders, or pain.
It is well established that a particular CNS disorder may involve complex interactions of multiple neuroreceptors and neurotransmitters, and, conversely, a single neuroreceptor may be implicated in several CNS disorders as exemplified by the serotonin (5-hydroxytryptamine or “5-HT”) and dopamine (3,4-dihydroxyphenyl-ethylamine or “D”) systems outlined in Table 1. Many of the receptors that are distributed in the brain are also found in other areas of the body including gastrointestinal (GI) tract, blood vessels, and muscles, and elicit physiological response upon activation by appropriate ligands.
TABLE 1Receptor Subtypes, Distribution, and Associated CNS Disorders.ReceptorImplicated DisordersSertotonin5-HT1AAddiction, aggression, anxiety, appetite, memory, mood, erectile dysfunction, sexual behavior, sleep, sociability.5-HT1BAddiction, aggression, anxiety, learning, memory, mood, penile erection, sexual behavior.5-HT1DAnxiety, locomotion, vasoconstriction.5-HT1EUnknown.5-HT1FVasoconstriction.5-HT2AAddiction, anxiety, appetite, cognition, learning, memory, mood, perception, psychosis, sexual behavior, sleep.5-HT2BAddiction, anxiety, appetite, GI motility, sleep, vasoconstriction.5-HT2CAddiction, anxiety, appetite, GI motility, locomotion, mood, perception, penile erection, sexual behavior, sleep.5-HT3Addiction, anxiety, GI motility, learning, memory, nausea.5-HT4Addiction, anxiety, GI motility, learning, memory, mood, respiration.5-HT5ALocomotion, sleep.5-HT6Anxiety, cognition, learning, memory, mood.5-HT7Anxiety, memory, mood, respiration, sleep.DopamineD1Addiction, ADHD, autism, bipolar disorder, dissociative disorder, depression, eating disorder, impulse control disorder, obesity, obsessive compulsive disorder, Parkinson's disease, somatoform disorder.D2Addiction, bipolar disorder, depression, mania, Parkinson's disease, schizophrenia, tardive diskinesia.D3Addiction, ophthalmic disorders, schizophrenia.D4Bulimia, erectile dysfunction, schizophrenia.D5ADHD, autism, depression, dissociative disorder, eating disorder, impulse control disorder, movement disorder, obsessive compulsive disorder, somatoform disorder, tardive diskinesia,.
The rational drug design process is based on the well established fundamental principle that receptors, antibodies, and enzymes are multispecific. Topologically similar molecules will have similar binding affinity to these biomolecules, and, therefore, are expected to elicit similar physiological response as those of native ligands, antigens, or substrates respectively. The aforementioned principle, as well as molecular modeling and quantitative structure activity relationship studies (QSAR) are quite useful for designing molecular scaffolds that target receptors in a “broad sense.” However, they do not provide sufficient guidance for targeting specific receptor subtypes, wherein subtle changes in molecular topology could have substantial impact on receptor binding profile. Moreover, this principle is inadequate for predicting in vivo properties of any compound. Hence, each class of molecules should be evaluated in its own right not only for receptor subtype affinity and selectivity, but also for efficacy and toxicity profiles in in vivo animal models. Thus, there is a sustained need for the discovery and development of new drugs that target neuroreceptor subtypes with high affinity and selectivity in order to improve efficacy and/or minimize undesirable side effects.
Serotonin and dopamine constitute the two major neurotransmitters that are implicated in numerous disorders. To date, fourteen serotonin and five dopamine receptor subtypes have been isolated, cloned, and expressed. The present invention is directed at targeting the serotonin 5-HT2A and D2 receptor subtypes for the treatment of CNS disorders that may be implicated by these receptor subtypes, including schizophrenia (cf. Table 1). Schizophrenia is an insidious mental disorder that affects about 1% of the world population. In the United States, the economic and social impact of this disease is enormous, and the cost of hospitalization, treatment, and medications coupled with loss of employment exceeds 60 billion dollars [4]. Schizophrenia manifests itself in two distinct, complex, and diverse symptoms. Positive symptoms comprise hallucinations, delusions, incoherence of speech, passivity, withdrawal, and incongruity of emotions. The negative symptoms include poverty of speech, reduced emotional response, inability to feel intimacy or initiate social contacts, lack of motivation, underachievement at school or work, and attention impairment. The overall description of the positive symptoms, according to clinical psychiatrists, is that it is a distortion or exaggeration of normal behavior while negative symptoms represent a diminution or loss of normal function.
Schizophrenia has been postulated to be the result of neurotransmitter dysfunction. In particular, 5-HT2A and the D2 receptors have been the most implicated in the etiology of Schizophrenia. Drugs that target dopamine receptors are referred to as ‘classical antispsychotics’, and include chlorpromazine (Thorazine) and haloperidol (Serenace). A serious shortcoming associated with the dopamine hypothesis is the fact that a large percentage of the patients do not respond to the first-time treatment with such drugs. Therefore, an alternate neurotransmitter hypothesis, known as the ‘serotonin hypothesis,’ has been proposed, and the selective 5-HT2A antagonist, ketanserin, has been effective in alleviating the negative symptoms of Schizophrenia [5]. Because the central dopaminergic and serotonergic pathways are connected anatomically, and interact functionally in the ventral tegmental and the prefrontal cortex areas of the brain implicated in schizophrenia, a combination serotonin receptor and dopamine receptor antagonist was found to alleviate both the positive and negative symptoms as well as movement disorders in schizophrenic patients [6-9]. This observation provided the impetus for the development of an integrated molecular entity (referred to as ‘atypical antipyschotics) such as clozapine and olanzapine that target both 5-HT2A and D2 receptors. The serotonin-dopamine antagonist (SDA) hypothesis postulates moderate D2 receptor blockade for the reduction of positive symptoms, and potent 5-HT2A receptor blockade for attenuation of the negative symptoms and movement disorders.
Rajagopalan [10, 11] disclosed pyridoindolobenzodiazepine derivatives A-H, but the compounds bearing other heteroatoms such as O, S, SO, or SO2 instead of NH in the B ring belong to novel heterocyclic systems that have not been disclosed before. The carbon analogs (X═CH2) in the B-ring of A-H have been disclosed by Adams and De Witt [12, 13].
Moreover, as mentioned before, the receptor binding and pharmacological properties are very sensitive to the overall molecular topology, and these properties cannot be readily predictable just from the molecular structure. For example, the regioisomers A,C and B,D as well as their corresponding cis- and trans-reduced analogs E,F and G,H in both azepine and diazepine systems display different receptor binding profiles and activities.